Due to the inherent water-insolubility of long-chain hydrocarbons, the parenteral provision of long-chain fatty acids such as the omega-3 fatty acids (e.g., the 18-carbon alpha linolenic acid, or ALA; the 20-carbon eicosapentaenoic acid, or EPA, and the 22-carbon docosahexaenoic acid, or DHA, and the 22-carbon docosapentaenoic acid, or DPA), and the omega-6 fatty acids (e.g., the 18-carbon linoleic acid, or LA, and the 20-carbon arachidonic acid, or AA), and the omega-9 fatty acid (e.g., the 18-carbon oleic acid, or OA), can require a triglyceride-based, oil-in-water emulsion delivery system for safe administration by the intravenous route of administration. A similar problem relating to water-insolubility is also encountered with medium-chain fatty acids (i.e., caprylic acid, capric acid), a common issue with hydrocarbons. Although some of these fatty acids are available as ethyl esters, there is no clinical experience demonstrating their safety upon intravenous infusion, and there are significant stability and toxicity concerns when they are prepared as sterile lipid injectable emulsion dosage forms.
To illustrate the stability challenges of injectable emulsion formulations as they relate to solubility or miscibility as homogenous dispersions, there is, for example, an approximate 100-fold difference in the aqueous solubility of the 8-carbon saturated fatty acid (FA), caprylic acid (0.7 g/L), compared to the 16-carbon saturated fatty acid FA, palmitic acid (0.007 g/L). Thus, not surprisingly, aqueous solubility worsens with increasing numbers of carbon atoms. The insolubility or immiscibility between two liquids (e.g., oil and water) gives rise to competing adhesive forces, or tension, between the liquids at their interface, keeping the liquid phases separate from one another. Miscibility of the two liquids can be determined by measuring the interfacial tension that exists between them, and the less miscible they are, the higher the tension at these liquid interfaces. As an example, the interfacial tension between caprylic acid, an 8-carbon compound, and water, is approximately 8.2 dyne/cm, whereas for the 18-carbon oleic acid against water it is nearly twice as high at 15.6 dyne/cm. Thus, triglyceride-based, oil-in-water emulsions are the only established vehicles for safely providing adequate amounts of non-polar, medium- and long-chain FAs intravenously, since it can be desirable for all such infusions to be miscible with blood upon injection, given its polar (water-soluble) characteristics. Moreover, as triglycerides, the clinical toxicology concern regarding the metabolic rate of formation of parenteral free FAs in the blood stream upon metabolism, thus producing systemic toxicity, is mitigated, as compared to the faster rate of release from lower molecular weight ethyl esters. Hence, the triglyceride oil is in the dispersed or internal phase and water is in the continuous or external phase. In contrast, water-in-oil emulsions cannot be given intravenously, as the oil phase is now in the external phase, which dictates the physical properties of the emulsion, and hence such emulsions would be immiscible with blood. This could lead to a potentially fatal intravascular embolism.
Parenteral oil-in-water emulsions also allow water-insoluble drugs and/or nutrients to be incorporated into the dispersed, or internal, oil phase that is distributed throughout the continuous, or external, aqueous phase. These two phases are made miscible by lowering the interfacial tension between oil and water by using an amphoteric emulsifying agent, such as egg phospholipids. Several injectable nutritional and drug emulsions are widely used in this manner in the clinical setting. Once formulated, it is imperative for the intravenous emulsions to remain physically stable, i.e., homogeneously dispersed submicron oil droplets in the continuous aqueous phase—otherwise separation of the oil phase from the water phase may lead to embolization from the formation of coalesced, large-diameter (>5 μm) fat globules in the microvasculature. This may result in increased risk of morbidity (e.g., capillary embolism, cellular damage from oxidative stress, and accumulation of fat in the liver and accompanying hepatic dysfunction evidenced by elevated liver enzymes) and possibly, mortality. In the physiologically compromised critically ill, the risk of harm from an unstable intravenous emulsion is greatly heightened in this setting.
Direct infusion of FAs into the bloodstream is potentially dangerous, and the free FA concentration in current lipid injectable emulsions for infusion is limited (Driscoll, 2006). All injectable oil-in-water emulsions containing medium-chain FAs (e.g., caprylic acid) and long-chain FAs (e.g., LA, EPA and DHA, etc.) for clinical use are derived from plant or marine oil triglycerides. Each triglyceride source has a distinctive FA profile with some oils containing high amounts of certain FAs, such as: a) linoleic acid (i.e., soybean oil, ≧50%), b) caprylic acid (MCT oil, ≧70%), c) oleic acid (i.e., olive oil, ≧80%). But for sources of fish oil triglycerides, there is a unique and significant pharmaceutical issue relating to quality (i.e., concentrations of the omega-3 FAs, EPA and DHA), which may have clinical implications given their potential therapeutic use to treat various diseases. Official pharmacopeias, which set the standards for drug purity and safety in various countries, have provided separate drug monographs for the concentrations of EPA and DHA in fish oil triglycerides. For example, the European Pharmacopeia (EP) wrote the first monograph (EP 1352) in 1999 (“Omega-3 Acid Triglycerides”). In it, the concentrations of the two principal bioactive omega-3 FAs, EPA and DHA, expressed as triglycerides, are specified to have a minimum sum concentration of 45 percent, and further, that the total of all omega-3 FAs have a minimum concentration of 60 percent. Six years later in 2005, EP 1912 was adopted (“Fish Oil, Rich in Omega-3 Acids”). In this monograph, the minimum concentration of EPA and DHA, also expressed as triglycerides, is required to be 22 percent (with a specified minimum EPA content of 13 percent, and a DHA concentration of 9 percent), and the total of all omega-3 FAs must have a minimum concentration of 28 percent. Hence, two active pharmacopeial monographs exist with EP 1912 requiring only approximately one-half the minimum concentration of omega-3 fatty acids as that stipulated in the original EP 1352 monograph.
During a laboratory investigation of commercially available products, a comparison of the FAs profile of two formulations revealed that although one formulation contained approximately 50% higher concentrations of total fish oil triglycerides than the other formulation (i.e., 15% vs. 10%), it contained approximately 50% lower concentrations of the certain bioactive omega-3 fatty acids, EPA and DHA (Driscoll et al, 2009). Consequently, the product with the lower EPA and DHA concentrations had higher amounts of other long-chain saturated FAs (e.g., myristic, palmitic and stearic acids). Although the formulations are routinely used for acutely ill patients, the FAs profiles are not therapeutically equivalent. Thus, two European manufacturers opted to apply separate EP monographs for their commercial omega-3 FA-containing injectable emulsion products. The discrepancy between these emulsion formulations continues today. Since there is a potentially clinically significant pharmacological/therapeutic role of fish oil (vis-à-vis the EPA and DHA concentrations therein), well beyond its nutritional indications, the different omega-3 FA contents of the different fish oil triglyceride sources included in these products can require careful calculation to ensure that therapeutically effective dosages of omega-3 FAs are prescribed for the desired clinical effects. When they are prescribed as a therapeutic (vs. nutritional) agent, a case can be made that for intravenous administration, it can be beneficial to use the purest (most concentrated) form of omega-3 FAs-containing oil in injectable emulsions, especially for critically ill patients. This may be particularly true for all current sources (plant or marine) of parenteral triglycerides since they all contain several unnecessary and/or undesirable FAs. For example, the 16-carbon saturated FA, palmitic acid, is present in soybean oil, olive oil and fish oil in concentrations approximating 10% of the total FAs profile. Excessive amounts of long-chain saturated FAs (≧14 carbons), such as palmitic acid in the diet (or present in the less refined emulsions), for example, can be pro-inflammatory, and can interfere with glucose uptake by skeletal muscle (Lee et al, 2006). In critically ill patients, glucose intolerance (i.e., hyperglycemia) is a clinically significant risk factor for increased morbidity and mortality (Driscoll and Bistrian, 2012). Hence, seeking a highly purified and enriched source of selected FAs (as MCTs and LCTs) for parenteral administration is desirable.
In the various plant and fish oils included in current lipid injectable emulsion products, more than 15 different FAs, containing from 6 to 22 carbons (Wanten and Calder, 2007), are present on a triglyceride or triacylglycerol backbone at positions sn-1, sn-2 or sn-3. These include both saturated (no double bonds) and unsaturated (one or more double bonds) FAs, and the greater the number of double bonds present, the greater the risk of oxidative degradation. Fatty acids are described using a specific nomenclature involving three general terms: 1) the number of carbon atoms; 2) the number of double bonds; and, 3) the carbon atom containing the first double bond. The source of FAs (plant or marine) determines the final FA profile. For example, processed coconut oil used to make MCT oil is a rich source of saturated medium-chain FAs, caprylic acid (˜75%) and capric acid (˜25%). Processed soybean oil is a rich source of unsaturated FAs, including omega-6 FAs (linoleic acid, ˜50%), omega-9 FAs (oleic acid, 25%), and omega-3 fatty acids, (alpha linolenic acid, ˜10%). Processed fish oil is rich in omega-3 FAs (sum of EPA and DHA, ≧22% to ≧45%).
The medium-chain, saturated FAs contain no double bonds, come from plant sources such as coconut oil, and are present as medium chain triglycerides (MCTs). They primarily include the 8-carbon caprylic acid (˜75%), denoted simply as 8:0, and the 10-carbon capric acid (˜23%), denoted as 10:0 (Senior, 1968). Currently, there are no commercial lipid injectable emulsions made exclusively from MCTs, but rather MCTs are present in various products in a mixture with other oils such as soybean, and/or olive and fish oils. Initial concerns of clinically significant ketogenesis arising from the metabolism of MCTs were not realized based on its vast clinical experience with them over the last 25 years when given in daily doses of 50 to 100 g per day as a parenteral nutrition supplement. In these cases MCTs were prescribed as a dense calorie source, and when given with hypertonic glucose as part of a parenteral nutrition support regimen, the resulting hyperinsulinemic response upon infusion mitigates ketogenesis (Bach et al., 1989). With lower insulin levels, however, a modest ketogenesis is observed, which can be therapeutically desirable in certain patients. For example, ketogenic diets have been suggested for certain patients refractory to neuroleptic therapy for seizures, as well as for neuroprotection in various neurological diseases (Maalouf et al, 2009), which may include traumatic brain injury of varying origin.
Omega-3, -6, and -9 FAs are classified as unsaturated fatty acids, containing one or more double bonds. The three main families of unsaturated FAs important in human metabolism include 1) the omega-3's, e.g., alpha-linolenic acid, or ALA, containing 18 carbons and 2 double bonds beginning on the 3rd carbon (hence, “omega-3” or “n3”) from the methyl end of the hydrocarbon chain, denoted as 18:2n3; eicosapentaenoic acid, or EPA, containing 20 carbons and 5 double bonds beginning on the 3rd carbon, denoted as 20:5n3; and, docosahexaenoic acid, or DHA, containing 22 carbons and 6 double bonds beginning on the 3rd carbon, denoted as 22:6n3; and, docosapentaenoic acid, or DPA, containing 22 carbons and 5 double bonds beginning on the 3rd carbon, denoted as 22:5n3; 2) the omega-6's, e.g., arachidonic acid, or AA, containing 20 carbons and 4 double bonds beginning on the 6th carbon (hence, “omega-6” or “n6”), denoted as 20:4n6 and linoleic acid, or LA, containing 18 carbons and 2 double bonds beginning on the 6th carbon, denoted as 18:2n6; and finally, 3) the omega-9's (e.g., oleic acid containing 18 carbons and 1 double bond beginning on the 9th carbon (hence, “omega-9” or “n9”), denoted as 18:1n9. The omega-3 and omega-6 FAs are classified as polyunsaturated (more than one double bond), while the omega-9 FAs are monounsaturated.
In human metabolism, Western diets are disproportionately high in omega-6 FAs (Simopoulos, 2009). Because the cell membranes are composed of lipids, they are a reflection of recent dietary intake of various fats. Moreover, all cells have a finite lifespan in the circulation, such as, for example: approximately 120 days for red blood cells; approximately 10 days for platelets; and approximately 6 hours for white blood cells. In the case of white blood cells, once they are released from the bone marrow or lymphoid tissues, the short time in the circulation reflects the fact that they are merely being transported to local tissues in response to an immunogenic stimulus. But once at the site of injury, they may survive for as long as a few days during phagocytosis. Thus, cells of the body are constantly turning over with dietary intake of fats being continually used to construct plasma cell membranes during the process of hematopoiesis. In addition, there is a more rapid interchange of FAs in cell membranes of circulating cells. The dietary sources of FAs in human metabolism are important because the body produces endogenous chemical mediators derived from these membrane-bound lipids. This would include, for example, the eicosanoids and leukotrienes, which have a profound effect on the body's metabolic response to injury. The bioactive mediators produced from omega-6 fatty acids include specific eicosanoids, which have more pro-inflammatory/pro-coagulable properties deriving from the “2-series” of prostglandins and thromboxanes, which are highly vasoactive. As well, production of leukotrienes of the “4-series”, also from dietary omega-6 FAs in cell membranes, heightens the immune response, increases oxidative stress, and promotes inflammation. Therefore, in this case, altering the sources of daily intakes of dietary lipids, with an emphasis on increasing the absolute intakes of omega-3 FAs, causes a metabolic shift to the “3-series” eicosanoids and “5-series” leukotrienes, which are less vasoactive, and therefore less inflammatory and immunogenic. Consequently, facilitating these changes at the cellular level by the pharmacological dosing of precise amounts of parenterally administered selected FAs (in this case, omega-3's) may ultimately be associated with improvements in morbidity and mortality in a number of clinical conditions involving acute and severe catabolic stress. Furthermore, there are resolvins made from EPA and DHA, as well as neuroprotectins made from DHA that have active anti-inflammatory roles to resolve inflammation. Lipoxins from AA can, under certain circumstances, play a similar role. For example, incorporation of omega-3 FAs into cell membranes, and thus significantly altering eicosanoid metabolism with potential therapeutic implications, is best measured in red blood cells (RBCs). They have a long lifespan, exhibit the lowest biological variability, and the omega-3 FAs concentrations in RBC membranes is not altered by the “fed state”. From these observations, the “Omega-3 Index”, which is expressed as the sum of EPA and DHA as a percentage of total identified RBC FAs, is useful, with a defined range of 4% to 8% having therapeutic implications (Harris, 2010). For instance, risk of major cardiac events is increased when EPA and DHA levels fall below 4%, whereas cardioprotection was observed when levels were above 8%.
In the critically ill, there are numerous ongoing metabolic insults from various sources. For example, certain patient populations, such as those with head trauma, 3rd degree burns, long-bone fractures and culture-confirmed blood infections (sepsis), have a very high level of metabolic stress, as evidenced by, for example, standard severity-of-illness scoring systems (e.g., Acute Physiology and Chronic Health Evaluation, or APACHE II, Simplified Acute Physiology Score or SAPS II, and the Injury Severity Score, or ISS). The scoring criteria include various patient factors upon admission to the intensive care unit (ICU), e.g., vital signs and certain blood values, but in all such cases of severe metabolic stress, patients universally have general inflammation, otherwise known as the Systemic Inflammatory Response Syndrome (SIRS), an indicator of the intensity of the metabolic response during critical illness, along with elevated blood levels of C-reactive protein. During this time, such patients are highly catabolic, i.e., have pronounced loss of protein from skeletal muscle to support the metabolic response to injury (e.g., protein breakdown to provide gluconeogenic amino acids to meet heightened energy needs). Hence, the loss of lean tissue (skeletal muscle proteolysis), which represents the metabolically active body cell mass, is a major component of the body's response to injury and/or infection, and ultimately, a crucial component in the recovery from critical illness. In the well-nourished patient, such losses can be tolerated for longer periods without nutrition support intervention (parenteral and/or enteral), compared to the patient who is moderately to severely malnourished. Lean tissue losses can be estimated from a measurement of urea nitrogen from a 24-hour urine collection. Every 1 gram of nitrogen lost represents approximately 30 g of lean tissue. Thus, critically ill patients with a 24-hour nitrogen loss of ≧15 g/day (approximately equal to one pound of hydrated lean tissue daily) would be considered to be in severe catabolic stress. Not surprisingly, in the case of pre-existing malnutrition now accompanied by critical illness, the time for intervention before significant clinical complications occur is substantially shorter and can require immediate metabolic attention. Judicial provision of parenteral and/or enteral nutrition support (i.e., permissive underfeeding) is often instituted during this time, and begins to offset the extraordinary protein losses, but it is of reduced efficacy and/or benefit until the underlying stress response remits (Driscoll and Bistrian, 2012).
During this period of severe metabolic stress, the function of vital organs (e.g., brain, heart, lungs, liver and kidneys) may be compromised, and this is especially true if organ impairment is present prior to admission to the ICU. For example, patients may be at increased risk because of longstanding diseases such as asthma, chronic obstructive pulmonary disease (COPD), chronic renal failure (CRF), congestive heart failure (CHF) or end-stage liver disease (ESLD). Moreover, the clinical situation may be acutely worsened in the ICU because of iatrogenesis. That is, during treatment of the critically ill, certain medical interventions may worsen organ function. For example, acute fluid overload from large-volume intravenous fluids administered for intravascular resuscitation and to maintain hemodynamic stability may cause clinically significant changes in serum electrolytes and acid-base balance affecting cardiac function, which may increase the need for mechanical ventilatory assistance, and may worsen kidney function. Thus, compromised or failing vital organs (i.e., acutely, chronically or both) accentuates the metabolically stressed state and likely increases medical complications affecting clinical outcome.
Finally, the pharmacokinetics and pharmacodynamics of the various drugs commonly prescribed to critically ill patients are also affected during severe metabolic stress. Clearly, the disposition of the drugs throughout the body and delivery to their target site(s) of action (i.e., pharmacokinetics), will be altered. That is, changes in blood flow will greatly influence the successful delivery of sufficient concentrations of drug to its site of action in order to exert its therapeutic effects (i.e., pharmacodynamics). Alterations in the circulatory system may occur as part of the physiologic response to active stress. For example, in a hemodynamically unstable state, the body re-directs blood flow from the splanchnic circulation and skin to support vital organs and functions; during adult respiratory distress syndrome (ARDS), hypoxic vasoconstriction occurs to avoid attempts by the body to ventilate poorly perfused segments of the lung; and, serum albumin precipitously falls during acute metabolic stress and inflammation, thus altering drugs that are highly plasma protein bound, which may increase the toxicity of drugs which have a narrow therapeutic index (Driscoll et al, 1988). These and other adaptive physiologic responses to severe metabolic stress are consequential to outcome, and may also affect the safety and efficacy of drug therapies during critical illness, which may be amenable to selected FAs therapies via specially-processed triglycerides from exemplary lipid injectable emulsion formulations in specific amounts and/or combinations.
Some reduction in the severely stressed metabolic state may be achieved by specifically-targeted medical interventions (e.g., optimized antimicrobial therapy for culture-confirmed microorganisms, aggressive diuresis and vasopressor infusions) and selected surgical interventions (e.g., excision of necrotic tissues, repair of major blood vessels and surgical drainage of abscesses). But in these circumstances, like nutrition support intervention above, the efficacy of such clinical maneuvers may be self-limiting and take several days to begin the healing processes. During this period of convalescence, the metabolic milieu maintains a “net” inflammatory state, which eventually wanes over time. It would be desirable to hasten the resolution time of the net inflammatory state, and subsequent healing process(es), therefore improving outcomes in the ICU.
Omega-3 FAs, and in particular EPA and DHA, have been subject to intense investigation as potential therapeutic agents in diseases associated with inflammation, oxidative stress, ischemia and immune function. The emerging cellular and molecular mechanisms that underlie the therapeutic effects of omega-3 FAs have been reviewed (Serhan et al, 2008). A recent review of the potentially wide-ranging clinical indications for these exemplary FAs has been published, showing that by increasing the supply of omega-3 FAs to alter the FA composition of cell membranes, there are profound downstream effects on the cellular response to metabolic stress (Calder, 2010). For example, the systemic anti-inflammatory properties of omega-3 fatty acids, via modulation of eicosanoid precursors (prostaglandins and thromboxanes) of the “2-series” to the less vasoactive “3-series” in cell membranes, can be dosed to treat a number of acute diseases of inflammation (e.g., systemic inflammatory response syndrome marked by elevated C-reactive protein levels in the critically ill) as well as chronic diseases of inflammation (e.g., rheumatoid arthritis). This metabolic modulation reduces the intensity of a prolonged and often over-exuberant, omega-6 FA-induced inflammatory response, which has pathological implications. In addition, the immune response is also favorably modified by omega-3 FAs supplementation by altering recruitment of neutrophils for phagocytosis by similar modulation of other important endogenous mediators, i.e., leukotrienes, from the relative hyperimmune “4-series” to the less immunogenic “5-series”. This, in turn, can favorably modify the intensity of the immune response, and reduce the accompanying oxidative stress from the production of reactive oxygen species during phagocytosis. Because of the metabolically important and common interplay of the physiological responses involved (inflammation, oxidative stress, ischemia and immune function), and the metabolic stresses from various etiologies (e.g., infection, trauma, burns, compromised vital organ functions, etc.), the safe parenteral provision and effective uptake of omega-3 FAs may have a clinically significant effect on therapeutic outcome. This may be particularly true when such provision is accompanied by effectively applied standard treatment regimens (e.g., antibiotics, hemodynamic stability, fluid, electrolyte and acid-base management, surgical repair, etc.).
Conventional, high molecular weight sources of omega-3 FAs, such as fish oil triglycerides, can contain various (10-15) saturated and unsaturated FAs that are found on the triglyceride backbone at positions sn-1, sn-2 or sn-3 as found in nature. Of these FAs present, less than half are of therapeutic importance. A more purified FA profile that contains a specific amount of a therapeutic FA or combination thereof, and thus is devoid of undesirable, and possibly deleterious FAs, is therefore desirable. For example, as described above regarding the two official monographs, EP 1352 and EP 1912, the omega-3 FAs fraction is only between 30 and 60% (respectively), whereas the remaining FAs comprise from between 40% and 70% (approximately). In contrast, and at present, an oral capsule dosage form of EPA and DHA provided as ethyl esters exists as an FDA-approved product “Lovaza™” indicated, “as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with very high (≧500 mg/dL) triglyceride levels”. This occurs presumably by reducing “the synthesis of triglycerides (TGs) in the liver because EPA and DHA are poor substrates for the enzymes responsible for TG synthesis, and EPA and DHA inhibit esterification of other fatty acids” (Lovaza, 2007). Further, it states: “Each one gram capsule of Lovaza (omega-3-acid ethyl esters) contains at least 900 mg of the ethyl esters of omega-3 fatty acids. These are predominantly a combination of ethyl esters of eicosapentaenoic acid (EPA—approximately 465 mg) and docosahexaenoic acid (DHA—approximately 375 mg)”. Thus, compared to the highest minimum limits for EPA and DHA of the European Pharmacopeia (i.e., EP 1352) of 45%, the concentrations of EPA and DHA in Lovaza™ are at least twice as high as the concentrations contained in current sources of fish oils that are approved for clinical use, and therefore they are of far greater purity. Application of an exemplary, highly purified selected FA or mixture of FAs, as parenteral triglycerides, may lead to a safer source, and more precise dosing of therapeutic FAs to target therapies for specific clinical conditions than presently available options. Moreover, given the higher purity of selected FAs, parenteral oil-in-water formulations containing various combinations of desirable FAs from purified triglyceride mixtures can be devised for parenteral administration in far smaller volumes than is possible using less purified sources or natural oil sources, which addresses another major clinical issue in critically ill, fluid overloaded patients (Lowell et al, 1990).
In other cases of acute illness, certain FAs may also be beneficial. During myocardial infarction, provision of omega-3 FAs may reduce ischemia in the coronary vessels. Severe hepatic steatosis that compromises liver function may be treated with omega-3 FAs. For example, patients with epileptic seizures that are refractory to anticonvulsant therapy may uniquely respond to the provision of medium-chain fatty acids that produce a mild, but therapeutic, ketogenesis. Thus, medical emergency situations that can require immediate intervention may also be amenable to targeted FAs therapy. Moreover, the neuroprotective effects of medium-chain FAs may be beneficial in traumatic brain injury, and potentially synergistic by the concomitant intravenous administration of omega-3 FAs.
At present, there are three general forms of triglycerides available for parenteral use as lipid injectable emulsions: 1) natural sources containing an array of various FAs (e.g., coconut oil with approximately 80% of the FAs profile containing 6 to 14 carbons, with approximately 10 to 13% as the medium chain FAs, caprylic acid and capric acid, in nearly equivalent amounts); 2) “processed” natural sources containing selected FAs (e.g., coconut oil that has undergone steam hydrolysis and double distillation, principally yielding caprylic and capric acid and comprising >95% of FAs that are re-esterified to glycerol forming “MCT Oil”); 3) structured triglycerides made from natural sources that are hydrolyzed to yield a unique FA profile (e.g., re-transesterification after random mixing of the selected FAs, yielding unique triglycerides that contain various amounts of each FA, depending on the starting proportions of each oil such as the former product known as Structolipid™ containing 64% soybean oil and 36% MCT oil (by weight).
In many clinical conditions, certain FAs may have therapeutic benefits, but may require highly specific doses of the selected FA(s). Of the three above options, there is no way to precisely deliver selected FAs for the intended parenteral FA therapy in a particular clinical condition. Thus, in all cases, either undesirable FAs or less precise FA concentrations severely compromise the clinical testing of FAs as pharmacological therapy for many acute disease conditions.